#13
Science by Newcastle Students
Latest science news ▪ The RNA world Prion diseases ▪ Plastic Waste Cleanup
E
ntropy. In the simplest terms, lack of order, or gradual decline into disorder. Whether it’s battling our messy desks or the effects of disorder within our bodies, we fight entropy all our lives in some form. Our bodies take the form of ordered structures, which have evolved over billions of years from the first RNA molecules. Large proteins are folded from noodles and blobs into molecular machines by chaperones, one improbable, ordered shape, out of endless possible inactive conformations. However, no systems of our body that keep order can stem the effects of time on our bodies. Chief among these is the disorder of DNA which can take place over our lifetimes, causing mutations which can lead to cancer, or take place over generations, leading to changes in species over time. We have to face the consequences, however, of our attempts to create order in the world around us. We blast the earth and extract oil and metal, modelling our world as we see fit with cars, skyscrapers, and plastic McDonalds toys. Yet those molecules we so carefully arrange are liberated, scattered in the atmosphere as greenhouse gases, or chunks of plastic reduced to nanoscale in the sea. Now we fight to clean up our mess. This issue collects stories of entropy, inside and outside our bodies. As always we hope you enjoy this issue, and are staying safe in these unprecedented times.
AA & AM 2020
THE TEAM EDITORS: Adam Azzi blogs.ncl.ac.uk/react
and Alethea Mountford LAYOUT: Janire Castellano Bueno
Want to edit, organise or design this magazine? Get in touch!
and Patrycja Ubysz NEWS EDITOR: Elizaveta Olkhova SUB-EDITORS : Joanna Ciafone, Christina Julius, Adam Azzi, Jess Leighton, Alethea Mountford, Justin Byrne, William Gan,
react.mag.team@gmail.com
Paola Lanzoni, Elizaveta Olkhova COPY-EDITOR: Sammy Waite
@react_magazine
BLOG MANAGERS: Terri Lau and Aisha Islam PUBLIC RELATIONS : Zoe Kirk-
facebook.com/react.mag
ham and Justin Byrne COVER: Patrycja Ubysz
Contents News 4 What’s new in science?
Paediatric oncology 8 The daily journey of an inpatient
Environmental effects in sperm 11 Consequences for next generation offspring
News What’s new in science?
4
Protein folding 13 Making better predictions
Cancer development 16 Disorder in the building blocks of life
Human evolution 18 Genetic Death of the Human Race?
Interview with Tamara Rogers 20 And her research in Astrophysics
Plastic in the sea
24
Entropy of plastic waste in the marine environment
Plastic at sea Entropy of plastic
24
Optogenetics
27
Controlling seizures using light
RNA world 30 From Chaos to Life
Book review 34 “All That Remains: A life in Death” by Sue Black
Prion diseases 36 Increasing disorder from a conformational change
Homeostasis
39
What happens when the human body loses order?
Optogenetics Controlling seizures
27
Pick of the web 41 Our favourite web cartoons
NEWS
The latest science scoop from Newcastle with Elizaveta Olkhova
Newcastle University joins the fight against Coronavirus As the COVID-19 pandemic escalates, it is time for scientific and medical field to come together and unite the effort to protect human population from the disease. While universities across the UK have shut down, including Newcastle, scientists have been working tirelessly to help the NHS and support the Public Health of England. The Faculty of Medical Sciences at Newcastle University has sent seven qPCR machines to help with screening of people with acute COVID-19 infections. Additionally, researchers at the FMS have sent out essential RNA extraction kits, which are required to yield viral RNA from patient saliva samples for further testing.
that could help identify antibodies against the virus in the serum samples of patients. Additional volunteering teams have been set up, such as driving teams that provide lifts to the NHS workers to eliminate any risks of infection on public transport. All of this is only a fraction of a coordinated and quick response from Newcastle University. Other faculties are also working hard to provide vital equipment to the Government and the NHS in an effort to battle the spread of disease.
731 people have signed up to help hospitals with virus testing, as well as with setting up a screening facility in the Faculty. This facility will assess novel commercial kits
4
{react} Issue 13 2020
blogs.ncl.ac.uk/react
Linking spillage of fat from the liver with type II diabetes Pioneering work at Newcastle University has previously shown that calorie restriction can modify or reverse type II diabetes. More recently, novel research into this topic looked at the fat molecules produced by the liver that circulate in blood. The authors were able to link the spillage of excess fat from the liver to a subsequent increase of pancreatic fat content. The pancreas contains enzymeproducing cells, including beta cells that synthesise and release insulin as a response to rising blood glucose levels. Elevated fat content in pancreas can block the function of beta cells and reduce insulin production as a result. Novel research hence directly correlates obesity and excess fat storage in liver to downstream pancreatic dysfunction. Authors were additionally able to demonstrate that patients who regained weight went on to redevelop blogs.ncl.ac.uk/react
diabetes type II, highlighting the importance of fat content control in this widespread disease.
Read the original research paper: https:// www.cell.com/cell-metabolism/fulltext/ S1550-4131(19)30662-X
Scientist who developed ‘Geordie’ anti-cancer drug Rubraca donates all proceedings to set up a charity fund .
Professor Nicola Curtin at Centre for Cancer, Newcastle University, was at the forefront of development of the novel anticancer drug named Rubraca and was awarded £850,000 for her life-saving research. Professor Curtin generously donated the gift to set up The Curtin PARP Fund at the Community Foundation. PARP in this case stands for Passionate About Releasing your Potential and this charity’s Issue 13 2020 {react}
5
NEWS goal is to support people in acquiring new skills and talents and help them reach their full potential with the ultimate goal of integrating these individuals in employment and education systems. Applications for funding are considered all year round with grants up to £3,000 available through Curtin PARP fund.
Visit Community Foundation website for more details: www.communityfoundation.org.uk/apply
Pathogenic bacteria may shed their outside wall to protect themselves against antibiotics Antibiotic resistance is an ever-growing and pressing issue, with even the most advanced and strong antibiotics failing in clinic. Deciphering the mechanisms of bacterial resistance to antibiotics may provide us with clues on how to develop more potent and effective antibiotics against persistent bacterial infections. One example of such an infection is a urinary tract infection (UTI), predominantly affecting women, which often becomes recurrent and challenging to treat with conventional antibiotics. It is commonly caused by a pathogenic strain of E. coli bacteria. E. coli have a ‘coating’ or a protective cell wall, capsule, which is made up primarily of polysaccharides. Targeting the synthesis and integrity of this outer wall has been one of the main mechanisms of action of antibiotics, including the first discovered antibiotic penicillin.
6
{react} Issue 13 2020
Dr Katarzyna Mickiewicz, who worked on the project, holding up an E. coli plate A group of scientists at the Centre for Bacterial Cell Biology (CBCB), Newcastle University led by Dr Philip Aldridge and Professor Jeff Errington have detected wallless E.coli bacteria in urine samples of the majority of patients experiencing recurrent UTIs. This provides evidence that in recurrent infections, the pathogenic bacteria can actively protect themselves from antibiotics by shedding their outside wall. Even more interestingly, it was found that E.coli have reverted back to a normal, wallpositive, state following the antibiotic treatment.
Nature Communications publication: https://www.nature.com/articles/s41467-019 -12359-3 Find out more about these stories and more on the Newcastle University website at www.ncl.ac.uk/press/news
blogs.ncl.ac.uk/react
blogs.ncl.ac.uk/react
Issue 13 2020 {react}
7
IN FOCUS
The Journey of a Paediatric Oncology Inpatient Emily Rowlands and Cherise Jensen When research projects are written up and published, the results are usually the key focus. This means that members of the public and other researchers only get to read about the background for the research and the impact of the findings. However, much can be learned from reflecting on the research process itself.
Our project investigated the overall cost of a febrile immunocompromised child’s stay in hospital. These are children at high risk of infection due to primary or secondary immune deficiency. After informed consent, we studied three children, all of whom were cancer patients undergoing chemotherapy and who had been admitted to the Great North Children’s Hospital with fever. In order to investigate the overall cost of their stay, we worked as a team of six to observe the journey of each patient in hospital. We watched from a desk outside each patient’s room and recorded information about every staff member involved in their care: this included who they were, what they did for the patient and how much time they spent with them. In addition to the cost of paying staff, this project also aimed to gain an insight into the emotional and financial costs of the stay in hospital to the three children and their families. As MRes and medical students of varying stages, we were amazed at the effort that goes into making the children’s 8
{react} Issue 13 2020
stay in hospital happier, and the variety of activities and support that they are offered. Even our supervisors, paediatric consultants Emma Lim and Marieke Emonts, were surprised at some of the experiences had by their own patients. Account of a typical day for a paediatric oncology inpatient The child wakes up with their parent or carer who has been provided with a bed to stay with them on the ward. From this moment, their day is filled with visits from both healthcare professionals and other staff with many important roles. We observed an actress who entertained the children by reading to them individually. She told stories with great enthusiasm, putting on voices for all the different characters. Later, the older children received a visit from the Youth Support Coordinator, who arranged whatever she could to make their stay in hospital happier, for example, a takeaway meal, a social activity, or a specific DVD to watch.
blogs.ncl.ac.uk/react
assistants with a range of jobs to do. For example, they might deliver medication, run tests, take observations and discuss pain and management plans. Domestic staff also spent a lot of time keeping patient areas clean, regularly changing beds, emptying bins, and cleaning bathrooms. Each patient was also provided with meals prepared in the hospital and served on the ward.
ID 165091170 © Veerapong Boonporan - Dreamstime.com
We saw younger patients get a visit from the Play Specialist, who would engage with them and keep them active through play. In addition, the hospital had a teacher who would liaise with the child’s own school to bring their normal schoolwork to their bedside. Because of their treatments, many children are too tired for this, but it gives them the opportunity to keep up with their learning when they can and minimises the impact of their time off school. We also saw visits from the Animations Tutor, who came to teach the teenage patients how to make animations on an iPad, and from volunteers offering creative activities such as pottery making. In the afternoon, a nurse might take the child into the playroom to add to their Beads of Courage. These are a series of beads on strings which represent each patient’s cancer journey. A new bead is added for every stay in hospital, every course of chemotherapy, clinic visit, general act of courage, and so on. Between these activities, patients were visited by doctors, nurses and healthcare
blogs.ncl.ac.uk/react
In the evening, other family members would often visit. This filled the ward with noise and life, with patients excited to see their parents, grandparents and boisterous siblings. Once the visitors had left and the children were asleep, some parents met up in an empty bay. Having met each other so many times and shared the experiences of their children’s frequent hospital admissions, they have formed close friendships and a community, and could be heard laughing raucously into the night. Having worked closely with healthcare teams for years in some cases, these parents have become true experts in their child’s condition and care. But their time together is valuable, allowing them to support each other and unwind at the end of another emotionally difficult day. Reflections Occasionally, as an observer, it is possible to forget that these children are sick. Their days are so busy and filled with activity that there is an overwhelming spirit and life on the ward. When it comes down to it, these are all children: fresh-faced, resilient children, whose main priority is still to play and have fun. However, unfortunately, we also observed children who were too weak to participate in activities. We noticed Issue 13 2020 {react}
9
IN FOCUS posters about how to order wigs, or about the Make a Wish Foundation. At these points we were reminded that these children are unwell and by being in hospital, they are isolated from their friends and family, meaning that they miss out on social activities and home comforts. Educationally, there may be an impact, as they miss multiple days of school. Luckily, the grades of the children we observed had not been impacted. Yet, some still felt disadvantaged socially when they returned to school, feeling that their friends were growing away from them. Parents also reported their child’s reduced enjoyment of school and missed GCSE exams. In addition, the parents and wider family of the patient are hugely affected. We were shocked to find out that the average cost to the family per admission exceeded £140 (for a stay of up to a week, but in some cases only a few days). This figure accounts for food and travel only, and ignored the cost of days taken off work and the resulting job insecurity. Aside from the financial aspect, we also realised that admissions can be a huge logistical problem for families. For example, parents who have other children have to consider alternative childcare, with the patient’s siblings often missing out on normal after school activities as a result.
Furthermore, some families have difficulty organising transport if they do not have a car. Many relatives, including parents, siblings, aunties, uncles and grandparents, experience significant anxiety about the patient and often travel far to visit. Conclusion As hospital staff are extremely busy, they do not get the opportunity to act as a fly on the wall and truly take in everything that goes on in their ward. Overall, observing the journey of three paediatric inpatients provided a valuable experience for us as students to gain insight into the patients’ perspective. Understanding more about what patients go through is key to becoming a compassionate healthcare professional. Learning more about the roles of different members in the team of staff caring for patients was also interesting. Although investigations, medications and treatments are all an important part of patient care, the small activities and kindnesses are what the patients themselves will remember, what will make a real difference to them during their stay, and potentially even speed up their recovery. When looking at it this way, it is clear why so much effort is put into keeping the children occupied with the wide, and sometimes surprising, range of visitors that we encountered over the course of our research.
This project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No. 668303.
10
{react} Issue 13 2020
blogs.ncl.ac.uk/react
Do changes in the environment affect sperm and next generation offspring? Maria O’Hanlon Within a single ejaculate there are sperm that exhibit phenotypic variation. This means that the sperm can differ in size, shape, behaviour or capabilities. Phenotypic variation can be caused by genetic or environmental factors but currently little is known about the consequence of these variations amongst sperm. If this phenotypic variation can be deciphered, this research might be exploited during IVF to use stronger sperm for better offspring. It is believed that the performance of sperm is under diploid control, influenced by both maternal and paternal chromosomes, however, it now it appears that there are other components at play. DNA is packaged into chromosomes; human cells usually contain 23 diploid pairs – one chromosome of each pair from each parent. For years, it was believed that diploid organisms can manipulate the extent to which their sperm and eggs experience selection. This is because animals produce sperm that are influenced by proteins and RNA, limiting the amount of selection that can take place amongst the sperm. Alternatively, the phenotypic variation may have a genetic or epigenetic basis. Epigenetic control largely relates to external changes to the genetic code. This could mean that it is under selection. Epigenetic control can mean the genes are affected by DNA methylation, when chemical groups
blogs.ncl.ac.uk/react
are added to the DNA, histone deacetylation, where chemical groups are removed from the DNA, and mi-RNA expression, where protein production is repressed.
Epigenetic control largely relates to external changes to the genetic code Epigenetic or genetic variation within one male’s sperm may lead to competition between different sperm phenotypes or characteristics, for the fertilisation of eggs. If there are slow sperm and faster sperm in one ejaculate, then the fast sperm will compete to reach the egg first. It has been questioned whether this could translate into different fitness effects in offspring. For example, if a fast swimming sperm fertilises the egg, would the offspring be faster than the children produced by fertilisation with Issue 13 2020 {react}
11
RESEARCH slow swimming sperm. Similarly, if sperm is longer lived, and an older sperm reaches the egg, this could result in increased longevity in the offspring. There have been studies involving animal models, such as sea squirts, salmon and zebrafish, showing that longer-lived sperm result in offspring that have a higher chance of surviving after birth. In sea squirts, it was found that longer-lived sperm produced offspring that had a higher early-life survival. In salmon, fertilisation that occurred via sperm with intermediate longevity had sired faster hatching offspring. Zebrafish offspring resulting from longer-living sperm had a 7% increase in survival and had a faster swimming potential. These studies showed that variation in the sperm characteristics affects offspring fitness, with longer- lived sperm resulting in embryos with increased survival and fewer embryos entering cell death. In fact, survival rate of the next generation was higher than would be expected with slower or shorter-lived sperm.
Studies have shown that longer-lived sperm result in offspring that have a higher chance of survival after birth These studies have helped to highlight the consequences of variation amongst sperm and the results may be applied to future medicine or treatments for infertility. If this pattern of stronger, longer-lived, and faster sperm can be translated into humans, it
12
{react} Issue 13 2020
may be possible to select sperm to use during IVF to produce stronger, better offspring. In the zebrafish study, the researchers selected the sperm that moved the furthest away from the original point of origin to use as the faster moving sperm. They also waited for longer to select the sperm that had survived to use as the longer-lived sperm. If these techniques could be used in human studies, then theoretically, specific sperm could be chosen to use during IVF. However, there are issues that surround this practice. Selecting sperm based on particular characteristics or phenotype could be moving us in the direction of direct genetic manipulation and ‘designer babies’, which is shrouded in ethical questions. The situation becomes further charged when we consider the potential benefits this could have for increasing the success of IVF. As it stands, the live birth IVF success rate is only approximately 40 percent. If better sperm were selected, this could potentially positively influence this rate. More research is needed to examine whether longer-living and faster-swimming sperm pass on certain beneficial characteristics to offspring in humans too.
blogs.ncl.ac.uk/react
Understanding Protein Folding: Making better predictions Paola Lanzoni Proteins are one of the main macromolecules necessary for life. They are encoded, by our DNA and play many roles at the molecular and cellular level, ranging from shaping cells to cell lysis. As soon as the sequence of amino acids is transcribed from the messenger RNA (mRNA), a cascade of intrinsic interactions aids to fold it into its secondary and tertiary structure. Finally, the folded protein may interact with other copies to form its quaternary structure, when it is ready and functionally active. Proteopathies are diseases caused by misfolded proteins, which displays defective functions in the organism. One known example of proteopathy is Alzheimer’s disease where misfolded proteins forms toxic and insoluble aggregates inside the brain, causing cell atrophy and leading to dementia. Helping proteins find their way Beyond correctly folding a protein, our cells need to cope with the requested time forthis process. Despite being a complex molecular event, the time scale by which most proteins are synthesised and folded inside our cells is impressive; seconds! Now, at such high rate of production, could a peptide randomly try its routes of folding, or should it be guided in the right direction?
blogs.ncl.ac.uk/react
And if it is, then where does this guidance come from? Many scientists have been trying to figure out this problem for decades now. In 1969 Cyrus Levinthal described the problem stating that, for a small protein to fold into its correct conformation at random, it would take the time equivalent to the age of the universe. There should be, therefore, a driving force guiding the protein to fold correctly. A solution to this question was proposed about 25 years later, with the suggestion of a folding funnel formed by an energy landscape, where its width is given by the entropy and its depth is the energy of the molecule. Here, entropy can be understood as the number of conformations a protein can assume. Once a polypeptide chain is translated by the ribosome, it travels down this funnel as correctly folded regions are formed, and slightly improves the energy gain and minimises its entropy, speeding up the process of folding We now know that for a given polypeptide sequence, folding occurs in a given order: its core is correctly folded into its secondary
Issue 13 2020 {react}
13
RESEARCH and tertiary structures followed by its surroundings. However, if the core is not folded correctly, a living cell can employ a few rescue mechanisms to help refold it or destroy the misfolded protein - in a healthy organism that is. Fooling all the laws of thermodynamics even further, proteins called “chaperones” can protect and mechanically aid the process. ..
How scientists “see” proteins and advances towards a protein folding “oracle” .
Techniques such as X-ray crystallography, nuclear magnetic resonance and cryoelectron microscopy help to identify protein structure experimentally, each one with its own limitations. The process of producing protein for these experiments does not only involve high financial investments and teamwork, but also a considerably large amount of time, ranging from a few months to a decade, depending on the complexity of the target molecule. Once characterised, the structure is deposited online to a
worldwide databank called Protein Data Bank (PDB). In an attempt to aid this process, computational chemists are applying efforts to develop molecular modelling software able to predict protein structure. This work only became possible after characterisation of how chemical bonds are formed and broken, and the development of a few physico-mathematical algorithms that calculate energy and entropy for these reactions. Nonetheless, these kinds of software are not self-sufficient. Starting with an amino acid sequence as input, algorithms rely on primary sequence similarity to work. Data from similar proteins previously characterised (by techniques cited above) is used to form a template in which the input sequence is then modelled. An intelligent breakthrough The ‘Critical Assessment of Protein Structure Prediction’ (CASP) is a
The protein folding funnel, illustrated by the folding of a lace.
14
{react} Issue 13 2020
blogs.ncl.ac.uk/react
Photo 135639012 © Forance - Dreamstime.com
competition directed at enthusiastic bioinformaticians. The challenge is to correctly identify the structure of experimentally known (but unpublished) proteins for which sequence doesn’t display similarity enough to find a template - 50% at least. In other words; to find the structure for proteins that could only be characterised experimentally.
Starting with an amino acid sequence as input, algorithms rely on sequence similarity The 2018 edition was a breakthrough for the Google DeepMind team, a UK-based startup. The debut team outperformed their experienced fellow competitors by employing a surprising strategy: artificial intelligence. Although it uses protein sequence similarity to find areas where possible “folding domains” are spotted, the software does not use any template. The team used two deep learning neural networks as a scoring system for their models, trained using nonblogs.ncl.ac.uk/react
redundant PDB entries. The algorithms were trained to predict two crucial spatial parameters in a polypeptide chain: distance between specific amino acid residues, and the angles formed between them. Mimicking our natural folding mechanisms as depicted by the folding funnel, the team automatically identified and fragmented the protein sequence into “foldable domains” to be designed separately by the software DRAW (image generator), followed by assembly into the full-length and optimisation of structure overall thermodynamics. Although we are still far from fully understanding the protein folding process to the point where we could predict a complete and accurate structure for any amino acid sequence, we have good reason to believe we will do so in the near future. However, because all algorithms need previous knowledge of protein structure, bioinformaticians would still be limited by the bottleneck of experimental results. We can now hope for even more collaboration between Structural Biology and other STEM areas. Issue 13 2020 {react}
15
FEATURE
Entropy and Cancer Development - Disorder in the Building Blocks of Life Alex Blain Every cell within your body contains the instructions for life in the form of DNA molecules made up of thousands of genes which instruct your body to make proteins. When your cells divide, your DNA must be replicated in order for the two resultant cells to have the correct amount of DNA. Replication is very tightly regulated through multiple complex processes. We can liken the normal DNA replication within a cell to the ice state of water, there is a definite structure therefore the amount of disorder and entropy is low. While the accuracy of replication is high, as you age your cells undergo multiple rounds of replication, and errors in DNA known as mutations can occur. Occasionally, these mutations can lead to the uncontrolled division of cells - this is cancer.
fails, a tumour can develop
cells. There are also genes that work as regulatory mechanisms within cells, which control cell division and prevent cancer from arising, these are known as tumour suppressor genes (TSG). As you have two copies of every gene (one from your father and one from your mother), it requires two mutations or “hits” to fully inhibit a TSG function. An example of a TSG is the TP53 gene, this makes a protein named P53 which is referred to as “the guardian of the genome”. P53 becomes activated in response to abnormal signals in the cell and triggers a self-destruct mechanism known as apoptosis. When both copies of TP53 become mutated more mutations can occur within the cell, allowing it to become cancerous. This single cancer cell can be likened to the liquid water, as the genes within the cell have been altered leading to a breakdown in regulation of cell signalling, disorder has increased but is still contained within a single cell.
When a mutation occurs it can affect the function of the protein produced by that gene. There are genes that when mutated can work to promote cancer, these are known as oncogenes and make proteins that are involved in driving the division of
At this stage the cancer cell is usually recognised by the immune system, as specialised cells circle through the body looking for infected or abnormal cells. When the immune cells recognise oddlooking cells, they attack and kill the abnormal cells as a defence mechanism to
When immunosurveillance
16
{react} Issue 13 2020
blogs.ncl.ac.uk/react
keep the body healthy and wellfunctioning. This is known as immunosurveillance. In an individual with a fully functioning immune system this process is usually successful, although this is not always the case. When immunosurveillance fails, a mass of cancerous cells known as a tumour can develop. As the tumour grows these cells now have to compete with each other for resources such as space to grow, or for nutrients such as oxygen. As the cancer cells divide some cells will acquire new mutations, meaning that within the tumour not all the cells will be identical. In a process similar to natural selection, cells that have advantageous mutations or features will survive and out compete other cells. The main population of cells are known as the dominant clone, and smaller cell populations are referred to as subclones. This fully formed tumour can now be likened to the gaseous state of water, as there are many cancerous cells with many different mutations leading to multiple gene signalling pathways to become altered, promoting cell survival and uncontrolled growth. The amount of disorder and entropy has increased at each stage of cancer development and has reached its peak with multiple pathways deregulated in multiple cells.
blogs.ncl.ac.uk/react
The level of complexity does not stop there, as the cancer cells can evolve to have increased movement they can then enter and pass through the circulatory system, lymphatic system or body cavities in order to spread and grow within a new site, in a process called metastasis. When patients are given therapy to kill off the cancer cells, the effectiveness of treatment is dependent on the type of cancer the patient has and the stage they were diagnosed at. When treatment is given it may be effective at killing off the majority of cells within the tumour, however, subclones can contain mutations which allow them to resist and survive the treatment. This small population of cells can then survive and grow into another tumour, this is known as a relapse. It is also becoming increasingly apparent that it is not just the cancer cells themselves that are important, new research suggests is also the cells which surround them that can aid the evasion of the immune system and can also affect treatment response. The goal of treatment is to remove all the cancerous cells, similar to refreezing water to make an ice cube; the particles realign and order is restored. Research into cancer development mechanisms is vital to the design of therapies which are more effective.
Issue 13 2020 {react}
17
FEATURE
Genetic Death of the Human Race? David Webb Without getting bogged down in the physical description of entropy, it is enough for our discussion to know that in some respects, entropy is the measure of disorder in a system. The second law of thermodynamics indicates a natural tendency for systems to progress from order to disorder. Biological systems locally create order in the form of recognisably structured organisms, but entropic processes will influence this order. How does entropy lead to evolutionary changes and ‘problems’ for species, including our own? Random mutation is a process that increases disorder and entropy. Natural selection often acts to prevent ongoing mutation, through removal of mutants that create genetic disorder and disrupt a trait. Selective pressures, i.e. conditions that cause natural selection, therefore can locally retain order for a genetically determined, adaptive trait. When these pressures are removed, it is predicted that the trait will most likely become less ordered, as random mutations will often lead to a loss of function for the gene in which they act. In the evolutionary history of organisms, it can be seen that where traits are not needed anymore they tend to be lost. Many of these have significant energetic costs and so significant negative selective pressures when no longer needed. However, as predicted above, a movement towards genetic disorder of the genes used in a trait 18
{react} Issue 13 2020
should be seen without any strong selective pressures. An interesting example comes from the several blind, cave dwelling forms of the fish species Astyanax mexicanus, which have independently evolved the loss of functioning eyes and loss of pigmentation. This loss of traits has been described as ‘regressive evolution’. Genetic evidence suggests that eye loss is consistent with selective pressures against the metabolic cost of eye development and that pigmentation loss is consistent with mutation and drift alone. Such ‘regressive evolution’ has implications for humanity. Modern medicines and technology could allow individuals bearing alleles that would otherwise be under large negative selective pressures to survive and reproduce. The number of deleterious (harmful) alleles in a population is known as the genetic load. Hypotheses for future trends in the human genetic load have been discussed and an increase in genetic load
Astyanax mexicanus
Credit: Grand-Duc (Wikipedia)
blogs.ncl.ac.uk/react
predicted, drawn from genetic evidence from humans and model organisms. Some deleterious alleles can presumably simply be lived with using technology, the very reason why selection upon them is relaxed, for example, the wearing of glasses for short-sightedness. This is not a new phenomenon, the genomes of humans dwelling within the arctic circle evolved to code for a body phenotype that is not suited for low temperatures, but did code for sufficient intelligence to get around these limitations through tool use (i.e. clothing and heating).
Whatever happens will all be part of human evolution However, it can definitely be argued that some genetic diseases are debilitating and reduce the quality of life of the sufferer, even though they may be managed sufficiently to keep the affected individual alive and able to reproduce. Screening and editing of the human genome could then provide a possible long term solution. Ethically this is a hotly contentious topic, with many grey areas, irrespective of technologically associated risks. Many people would consider screening against cystic fibrosis justifiable, but what about propensity for acne? If mutations that caused significant reductions in IQ began to accumulate then to what extent could removing these be justified? Especially if these genetic treatments were not free for all, this could lead to even greater rich-poor divides and greater stigma of having certain diseases, considered minor at present. Many of these questions remain theoretical will not need to be answered in blogs.ncl.ac.uk/react
the near future. Unfortunately, our first taste of gene editing of human embryos came from the claimed actions of He Jiankui, considered by many to be highly irresponsible and premature (around 120 Chinese scientists signed an open letter condemning the claim). This has brought concerns over the use of genome editing technology in humans to the forefront of scientific discussion. Ideas of genetic betterment of mankind also have a dark past. The eugenics movement of the 20th century believed in improving humanity by only encouraging reproduction of those with ‘positive traits’ – fuelling some of the reprehensible actions in Nazi Germany. Genome editing is tarred by this legacy, but the goal of curing genetic diseases need not be related to this ideology. Some form of greater control over our own genomes in the future is simply inevitable, in fact somatic gene therapy is already happening legally. Ultimately, in its own way, whatever happens will all be part of human evolution. As we gain the technological power to reliably cure and prevent genetic disease, we will be compelled to use it routinely in some form. For this reason, the human race need not be genetically ‘doomed’ from increases in disorder. Nevertheless, some difficult ethical decisions regarding the use of this kind of technology will need to be made in the future, both near and distant. Read more about He Jiankui and genome editing on the {react} blog: https://blogs.ncl.ac.uk/react/editing-our -dna-less-fantasy-than-reality Issue 13 2020 {react}
19
PROFILE
Interview with
Tamara Rogers Cassie Bakshani Dr Tamara Rogers is a reader of Astrophysics at Newcastle University and a Senior Scientist at the Planetary Science Institute.
She is specialized in
numerical simulations of hydrodynamics and magnetohydrodynamics (MHD) in stars and giant planets. Could you give our readers a lay summary of your research area and current work? I’m from California originally, so my degree was a double major in physics and astronomy, and my PhD is in astrophysics. In particular, I do big numerical simulations of fluid dynamics and magnetohydrodynamics, which is fluid dynamics with magnetic fields, in stars. I started out modelling the sun and I did my PhD looking at convection and magnetic field generation waves within the sun. I then switched over to looking at stars, but using the same fluid and hydrodynamic equations, which are the same as those you would apply to the ocean. Now I study big stars. These have a different structure to the sun and they’re a little more interesting from the perspective of waves. I study their internal gravity waves. I also study giant planets like Jupiter, but those that exist outside of our solar system called ‘hot Jupiters’. These are Jupiter-like planets found very close to their host stars. 20
{react} Issue 13 2020
What kind of data, if any, do you need to input into these simulations? Is any observational data required? I’m a numerical person and therefore my work falls under theory. I take the equations that we know must govern the system; in this case, Navier-Stokes, magnetic field and Maxwell equations. We know that stars exist for billions of years, but we can’t simulate this time frame, so the only additional data we need is from stellar structure equations. By solving these in one dimension it provides the reference state, which is the profile of a star at a given age. It’s one dimension as a function of radius because they are spheres. We input this data and then solve the 2D and 3D hydrodynamic equations around this. That’s all we need; we don’t start with observations and then try to reproduce them. We start with the equations and when we find something interesting, we collaborate with an observational team in Belgium who work with us to find a way for us to see that happening. blogs.ncl.ac.uk/react
Missing photo of Tamara
A snapshot of the interior of a blue supergiant. Waves originating deep inside the star break on the surface causing it to ripple and shimmer. How long does it usually take you to go from the basic equations to a simulated result? I use a 2D code that I wrote during my PhD that took around 6 months to a year to write. The simulations take, depending on a variety of factors, around 6 months to a blogs.ncl.ac.uk/react
year to run, or even a few months depending on how many parameters you change. That’s for 2D calculations. The 3D code took years to write and that was with guidance from my PhD supervisor. It took 20 years or so to develop the code and then I modified it to do slightly different things,
Issue 13 2020 {react}
21
PROFILE which took a couple of years. My postdoc has now made it fancier. Now we can use them indefinitely, but we optimise and parallelise them for different processors, so you end up running 3D codes for 6 months to a year. Hypothetically you could run them forever, but we have to find out what is happening and write papers too. 3D simulations also generate huge amounts of data and dealing with it takes a lot of time. What does a typical day look like for you? For the last few years I’ve been director of expertise for the applied maths and physics department, which is a very onerous job. The university closed its physics programme completely in around 2003, then it was rebooted in 2014 and I was hired in 2015. Most of my time is spent developing the physics programme and writing the strategy for the growth of physics. We have been recruiting and working out logistics. Because we’ve rebuilt physics here from the ground up, we’ve been able to do that with equality and diversity embedded from the beginning. This has been a huge passion of mine and it’s very important to me because there are so few women in physics in particular. There are also very few black students, but because there are so few it is difficult to work out the pipeline and distinguish where they drop out, because the problem is, they aren’t even coming in. We’ve instituted a number of things to help encourage women, which we hope will also address other underrepresented groups. The way we recruit is very progressive, we advertise that we have a really strong commitment to building this programme with diversity 22
{react} Issue 13 2020
embedded and candidates are required to give an EDI (equality, diversity and inclusion) talk when they come for interview. We take this extremely seriously, to the extent that if an individual messes up their EDI talk, we don’t care how good their research is. In the past, research trumped everything and that’s not the case anymore. When I came here 5 years ago I was the first woman hired in the department of applied math, now there are 4. We have a commitment to have at least 25% women academic staff, which puts us at the top of the Russell Group by a large margin.
In physics, women make up 20% of undergraduates, but this figure is similar at the professor level A recent study by Holman et al. 2018 investigated the citation bias and gender disparity in STEM subjects, highlighting physics as one of the fields where there remains a significant gender imbalance. Why you think this is and what you think needs to be done in order to encourage more women to pursue a career in this discipline? The thing with physics, which differs from maths, is that maths suffers from a leaky pipeline, women equate to 40% of undergraduates enrolled in maths courses, but this number is not reflected in professorships. In physics, women make up 20% of undergraduates, but this figure is similar at professor level so the drop off blogs.ncl.ac.uk/react
is not as bad for physics as it is for maths, but there’s just a very small number coming in in the first place.
You need to love it, because you’re going to spend your life doing it I think there are barriers for boys and girls to get into physics. Physicists are often depicted as dorks and most people just want to feel like normal people. The more there is a perception that genius is required rather than hard work, the fewer women apply to those subjects, and physics is definitely perceived like that. What we’re trying to do here is make sure the number from post doc to lecturer or professor doesn’t drop in our school. If there’s 25% at A level, we’re going to get them because we want Newcastle to be known as a place that does great physics, but is also the most diverse, vibrant department there is. By doing this, I think we actually get better people applying and hopefully our students can be role models that show that physicists are normal people that look much more like the wider population than a standard physics programme. At what point did you first develop an interest in astrophysics? When I graduated high school I went into the military to pay for college because I couldn’t pay for it otherwise. Then when I went to university, I thought I wanted to be an engineer, but then realised that I preferred physics. The great thing in the US is that you can change easily as long as you have studied the basics. In the UK, you get blogs.ncl.ac.uk/react
pigeonholed into a field quite early and then it can be much more difficult to make that change. I did a research experience as an undergraduate, which meant during summer I went to do research at the University of Oklahoma. From doing this I decided that astrophysics was much more interesting. In fact, even before that, whilst I was still in the military I took an astronomy class and asked the teacher where to go to study this; I applied to those places and got in. Astrophysics has all the same background as a physics degree, so it didn’t feel irresponsible to pursue it, it was likely I’d be able to get a good job. Do you have any advice for our postgraduate readers? You need to love it, because you’re going to spend your life doing it. The other thing is, be persistent, don’t give up and watch the TED talk on power posing. If you really do love it, then trust yourself and have confidence in yourself. If you’d like to learn more about Dr Rogers’ work in the Astrophysics group please visit the following website: https://www.solarphysicist.com/
Issue 13 2020 {react}
23
FEATURE
The Entropy of plastic waste through the marine environment Nicole Akhigbe In 1907, plastic was introduced to the world by a Belgian chemist called Leo Baekeland. In comparison to the natural materials used in the 20th century such as glass and wood, plastic was cheap, malleable, and durable. In the 1960s, researchers at sea started coming across more and more plastic in the waters they were investigating. This was when the slow decomposition rate of plastics became a cause for concern. The reason that plastic was so popular is now coming back to haunt us! Most plastics are non-biodegradable
This not only directly affects the shores it
because the polymers they consist of cannot
ends up on, but also the stock of fisheries
break down naturally. Even when exposed to various abrasive conditions, plastic still
nearby.
remains in its polymer form due to extremely strong carbon-carbon bonds. It remains in this polymer form after large dispersal and transportation, and can enter the marine environment in a variety of forms, even becoming bioavailable and being passed down the food chain.
On the other hand, ~80% of marine plastic comes from land-based processes. When plastic is not recycled it ends up in landfill sites; exposed to wind and rain. These act as ways of direct transport to marine environments or transport to rivers connected to the oceans. Once in the ocean,
So how does plastic end up in the marine environment? The most obvious offender is direct littering of plastic waste. Coastlines and beaches suffer from the mass litter of plastic, originally sold and brought to their locations. Large corporations that may transport their product at sea, or work in marine environments are also responsible for littering. For example, in 2012, the Japanese company: Sinopec lost over 160 tonnes worth of plastic pellets overboard.
24
{react} Issue 13 2020
blogs.ncl.ac.uk/react
currents contribute to the transportation of plastics, with microplastics tending to accumulate in gyres. A gyre is a large system of circulating ocean currents. The north Atlantic gyre and the north pacific gyre are home to significant quantities marine debris consisting of plastic waste, known as garbage patches. Many microplastics within these gyres sink to the ocean floor, either settling or being mistakenly consumed by benthic organisms, and thus continuing their movement through various marine food chains. Plastic microbeads in cosmetics such as toothpaste or facial scrubs, are able to travel from your sink to the ocean via drains.
“Microplastics IIb - Beach Clean up - 25g plastics / 22m That's 638KG along the Oregon Coast" by Wolfram Burner—CC BY-NC 2.0
Microplastics washed ashore
Fortunately, in 2018 the UK banned the production of microbeads in rinse-off
particles. Also, although a slow process, photodegradation and oxidation can cause
cosmetics, and countries such as the US,
embrittlement of marine litter via harsh UV
Canada and New Zealand have done the
light. This process of fragmentation
same. However, microbeads already present in the marine environment cannot
increases plastic’s ability to travel within the marine environment.
be retracted easily and can also end up in garbage patches.
Plastic microbeads in cosmetics such as
The intensity of fragmentation is entirely dependent on the specific journey a plastic product takes, meaning, the ‘end’ state of plastic in a marine environment ranges from large to microscopic sizes. So the
toothpaste or facial scrubs,
dispersion of plastic is able to reach wider
are able to travel from your
marine organisms by means of interaction,
sink to the ocean via drains
distributions and affect different sizes of ingestion and entanglement. For example, plankton at sea surface layer can mistake floating microplastics for food whilst
Large pieces of plastic that enter the marine
seabirds and marine mammals suffer from
environment are often broken down;
entanglement in plastic nets, as well as
consistent wave exposure can cause mechanical abrasion of plastics and
ingestion of macroplastics. However, it is estimated that 70% of plastic sinks to the sea
sediment action is able to break up larger
floor, resulting in microplastics having the
blogs.ncl.ac.uk/react
Issue 13 2020 {react}
25
FEATURE
A sea turtle tries to eat a plastic bag, mistaking it for a jellyfish ability to affect every organism in our oceans -from large sea mammals to benthic
these nanoplastics have very large surface areas that are able to bind toxic substances.
filter feeders. In fact, when plastic reaches
Little is known about nanoplastics and the
deep sea trenches its dispersion slows
effects of them are currently untraceable
down, making places such as the Mariana
due to their size.
Trench the ultimate sink.
The consumption of plastic within marine food webs af-
fects us humans who eat these organisms.
Many scientists are searching for new ways to retrieve plastic already in marine environments, but this has been deemed difficult to do without harming marine wildlife. Although there has been discoveries of bacteria being able to decompose plastics this won’t remove the plastic already in the oceans and will only
26
But the dispersal of plastic does not stop
be of use when recycling non-
there. The consumption of plastic within
biodegradable plastic in the future. For now
marine food webs affects us humans who eat these organisms. By the time plastic
the pollution of new plastic can be avoided if individuals like you and I work on
reaches us after being in a marine
cutting down our own plastic consumption,
environment it is at miniscule sizes, yet
and recycling plastics correctly.
{react} Issue 13 2020
blogs.ncl.ac.uk/react
Controlling seizures using light Adam Davison At least 50 million people around the world are diagnosed with epilepsy, making it the most common neurological disease that effects all ages. Epilepsy causes seizures which stem from excessive activity of the neurons inside the brain. Seizures are not only frightening but can also cause devastating instant and long-term effects on a person’s health. These include increased risk of depression, anxiety and memory loss. In some cases, people can even die suddenly following a seizure. With one third of patients not responding
networks. These networks are responsible
to conventional anti-seizure drugs, there is
for encoding information for all the
a pressing need for new treatments for this
processes our brains perform. Neurons
debilitating disease. Optogenetics, a
efficiently transmit information by
modern research technique which uses
electrically exciting each other, although
light pulses to change the activity of
this method of sending information comes
genetically manipulated neurons, has
at a cost, as too much excitation of neurons
revolutionised much of neuroscience
can trigger seizures. Uncontrolled
research. Many researchers believe that
excitation in even a small brain region can
optogenetics doesn’t just belong in the
start a domino effect where excitatory
science lab but is an epilepsy treatment of
activity spreads through a huge number of
the future. Researchers are developing
wired neurons throughout the brain. For
optogenetic epilepsy treatments that
this reason, every network in the brain
combine genetic manipulation with light-
contains inhibitory neurons that act to
emitting brain implants so that brain
supress the electrical activity of excitatory
activity can be controlled in real-time to
neurons. Your brain controls the
supress seizures. But is such a complex
dominance of these two opposing forces by
procedure feasible for the clinic?
the millisecond to prevent too much
Before scientists can design such optogenetic devices, they need to understand how seizures start and spread. This is not an easy task, as the brain contains billion of cells called neurons which are wired together in highly complex
excitation or inhibition of the brain’s networks. People with epilepsy have changes to their neurons that impair this balancing act, meaning subtle shifts in neuron activity can start a cascade of excitation which triggers seizures. In many
. .
blogs.ncl.ac.uk/react
Issue 13 2020 {react}
27
FEATURE forms of epilepsy, seizures are triggered by
discovery. They found that inserting these
a small region of epileptic brain tissue,
algae channels into the membranes of
called a focus, most often located in the
cultured rat neurons allowed them to
temporal lobe.
change the neuron’s activity, within
Optogenetics gives scientists a way to control this activity by manipulating the neuron’s own cellular machinery. Neurons are excited by the movement of positively charged ions through small protein channels embedded in their membranes. To ensure neurons are only active at the right
milliseconds, simply by shining specific light frequencies at them. In the following years, these researchers adapted this method to use in living rodents, where they controlled rodent’s whisker movements using similar optogenetic techniques.
moments, these channels only allow ions to
Optogenetics gives scientists
pass through when specific conditions are
a way to control ... activity by
met, such as at a particular voltage or in the
manipulating the neuron’s
presence of a certain chemical. In the early 1990s, it was discovered that algae were
own cellular machinery
able to move towards lighter regions due to specific light-responsive channels in their
This process revolutionised neuroscience,
cell membranes. In 2005, researchers at
and scientists soon started thinking about
Stanford University made a breakthrough
the enormous possibilities optogenetics has
Boston University
Illustration of a laser shining on a neuron 28
{react} Issue 13 2020
blogs.ncl.ac.uk/react
as a treatment for epilepsy. In theory, similar light-responsive channels can be inserted into the hyperactive neurons of a person with epilepsy alongside a device to deliver light pulses. When the brain produces electrical activity that signals an upcoming seizure, an electrode within the brain implant detects this and gives a quick burst of light that supresses the neuronal activity in the seizure-triggering region. This would be a game-changer in epilepsy
Created with BioRender
Mouse with optogenetics equipment
research as such a device could effectively
The clever science behind optogenetics
prevent a seizure before it even began.
means it has fewer problematic side effects
. . . . .
than conventional anti-seizure medications.
.
The clever science behind optogenetics means it has
fewer problematic side effects than conventional anti-seizure medications
Conventional drugs typically effect the whole brain, whilst optogenetics can be targeted to specific neurons within the seizure-triggering region by adding a DNA tag to the channel gene. Optogenetics also has the added benefit that it can change neuron activity only when required, whilst anti-seizure drugs effect the brain continuously.
But how can you deliver these channels into neurons deep within a person’s brain?
Whilst there are many details that need to
Strangely, it is viruses that hold the answer
be resolved before we will be seeing
to this problem. There are specific viruses
optogenetic treatments offered in hospitals,
which are excellent at getting access to
things are moving fast. At Newcastle
neurons and can be injected near the
University the CANDO project is a
epileptic region in the brain. These viruses
collaboration of researchers across multiple
can be manufactured as a package to carry
universities from different disciplines
the DNA that codes for the light-responsive
developing optogenetic devices to control
channels directly into neurons. Whilst this
seizures. In fact, the team expect to begin
may sound like science fiction, using
testing these devices in human clinical trials
viruses to transport DNA has already been
as soon as 2021. This research will hopefully
tested in humans for other diseases, such as
mean that, in the near future, many people
cystic fibrosis, and has been found to be
with currently untreatable epilepsy will be
safe.
seizure free.
blogs.ncl.ac.uk/react
Issue 13 2020 {react}
29
OPINION
The RNA world:
From Chaos to Life Christina Julius The Big Bang Theory is widely recognised as a likely theory of the beginning of our universe. But how did life come to be? Some argue that the first cells or biomolecules arrived on Earth via asteroids which is known as the Panspermia Theory. But conditions on the Early Earth were likely more conducive for molecular evolution, leading to biogenesis. Scientists have long tried to shed light on the events that must have preceded origination of the first “living” cells. One theory that prevails is the theory of the RNA World.
The Big Bang is estimated to have taken place about 15 billion years ago. Around 10 billion years later, our solar system and the Earth were formed. The first fossils (life forms such as stromatolites) were determined to be about 3.7-4.1 billion years old. But what happened during the period after our world was formed and before life came to be? Let’s zoom in. 4.5 billion years ago, our young planet suffered frequent collisions with large interplanetary bodies. One of those collisions is believed to have resulted
in the scatter that then became our moon. This is the beginning of the Hadean Earth. The Hadean is the time stretch between Earth and moon formation, and the end of the heaviest impact collisions about 4 billion years ago. At that time, the earth was very hot (about 230°C) but high pressure and a dense atmosphere of water vapour, carbon dioxide, ammonia and methane allowed oceans of liquid water to exist at these temperatures. Cells, or even more complex forms of life, could not have possibly existed at the time. Impacts of larger bodies frequently caused complete
Timeline from the Big Bang to Today 30
{react} Issue 13 2020
blogs.ncl.ac.uk/react
Painting “Formation of Earth’s continents” (1955) by Chesley Bonestell. This is how we can imagine a Hadean Earth to have looked like. vaporisation of oceans and strong pressure changes that would have destroyed all life. After such impacts it took about 3 thousand years for all ocean water to rain down onto the earth again. . . . . . . .
Under conditions like heat, pressure, and frequent energy spikes from lightning-like energy discharges and volcano eruptions, a variety of organic molecules would have formed. This process is also called abiogenesis, the formation of pre-life biomolecules. Life as we know it now is run by the interaction of the two main biomolecules: DNA and protein. DNA is the molecule that stores all genetic information. But it cannot carry out any active function beyond that. Most importantly, it cannot replicate itself. Thus, if DNA would spontaneously form on the Hadean Earth, one molecule of DNA would never become 2 molecules of DNA, it would simply disintegrate and die. Proteins
blogs.ncl.ac.uk/react
are the executors of replication, they assemble DNA from its monomers (building units) and carry out various other functions in the cell but cannot pass on their blueprint, and thus a spontaneously formed protein on Hadean Earth would also perish. Only the interaction of these two, the chicken and the egg, can maintain life. There is a third molecule in the mix: RNA. Within the central dogma of life, RNA is just an intermediate, a messenger between DNA (information) and protein (function). It’s meaning for abiogenesis, however, might be major. First of all, RNA can be a carrier of genetic information. In most organisms, it constitutes only as the information messenger, but some viruses still have pure RNA genomes, such as the Influenza, Ebola, or Rabies virus. Thus, although DNA is more stable than RNA, RNA as a sole carrier of genetic information is definitely Issue 13 2020 {react}
31
OPINION
32
possible. RNA is a close relative of DNA. Both nucleic acids are built up as chains of nucleotides, consisting of one of four varieties or bases. The only difference between the building blocks of DNA and RNA is one single oxygen atom, but this atom has a significant impact: While one DNA molecule associates with a second DNA molecule to form a double helix structure, one molecule of RNA folds and convolutes within itself, forming a “secondary structure”. This secondary structure can act as a scaffold for chemical reactions to take place. This was recognised already in the 1960s by scientists Leslie Orgel, Carl Woese and Francis Crick who first proposed that life could have evolved on the basis of RNA. But it took some technological progress before the existence of a chemically active RNA or “ribozyme” was proven in the 80s. These ribozymes act as a second substantial argument for the RNA World hypothesis.
that are favourable, and allow for survival. Replication means the copying of one complete molecule and its individual sequence of nucleotides. This sequence determines the secondary structure, or folding, of the molecule. If a mistake occurs during replication the sequence is altered, likely affecting function. Thus, novel ribozymes with new functions could perhaps be generated to create more complex intermolecular interactions, and potentially synthesis of DNA and proteins. Even now, the molecular machine responsible for carrying out protein synthesis in all living cells is a ribozyme: the ribosome.
Ribozymes are enzymes, or catalysts, made of RNA. A catalyst is a molecule which carries out and enhances a specific chemical reaction. All previously known biological catalysts have been protein-based enzymes. Although the existence of RNA that can replicate itself (an autocatalytic RNA replicase) has not been proven, it is conceivable (e.g. RNA viruses multiply using a protein RNA replicase). If we accept that this ribozyme RNA replicase existed, we can imagine the RNA World as governed by Darwinian Evolution just like the contemporary world. Darwinian Evolution describes the passing on of characteristics to the next generation, while environmental conditions select for traits
contemporary world.
{react} Issue 13 2020
If this ribozyme RNA
replicase existed, we can imagine the RNA World as governed by Darwinian Evolution just like the
Other evidence in support of the RNA World includes the existence of “RNA fossils”. Many cofactors and coenzymes (helper molecules) of metabolism carry a ribonucleotide part, adjacent to another functional moiety. The “useful” part of the cofactor is the non-ribonucleotide part which is utilised by enzymes to carry out chemical reactions. The function of the ribonucleotide moiety is not known. Many scientists argue that this nucleotide moiety might once have been used by ribozymes as a “handle” to bind to while it interacts with the “useful part”. blogs.ncl.ac.uk/react
The central dogma: DNA is transcribed into RNA which is translated into protein. DNA is depicted as a double helix made up of two DNA strands. RNA is depicted as a single stranded molecule with secondary structure. Protein is depicted in ribbon structure. Molecular Biologist Michael Yarus proposed that the ribonucleotide moiety might have served to integrate the cofactor into an RNA chain, while the nonnucleotide moiety could have interacted with or as part of primordial ribozymes. His hypothesis was based on his creation of such cofactor-bearing RNAs in his lab in the early 2000s – 9 years before they were discovered to exist in nature. Today we know that a nucleotide-containing cofactor can be found on some RNAs as a “noncanonical RNA cap” (NCIN) in all living cells. The enzyme which produces the NCIN-RNA cap is the same enzyme that produces all RNA, RNA Polymerase (RNAP). My research group at Newcastle University is currently studying this mechanism. It is currently unknown which function this structure has in today’s cells. Interestingly, all investigated RNAPs, from viruses, bacteria, eukaryotes and mitochondria, employ this mechanism. Potentially, NCIN-capping is a remnant
blogs.ncl.ac.uk/react
from the common ancestor in the RNA World which still serves a conserved but unidentified function. .
We can say that if there ever was an RNA World, we never really left it! Many arguments support RNA as our prebiological ancestor. RNA is the contemporary gene expression intermediate (mRNA), it can store genetic information (viral RNA genomes), and carry out specialised functions in the cell (ribozymes). Evidence accumulates in current research, e.g. on RNA fossils and non-canonical capping. At this point, we cannot with certainty say that the RNA World hypothesis is correct. But we can say that, if there ever was an RNA World, we have never really left it. Welcome to the RNA World! Issue 13 2020 {react}
33
REVIEW
Book review
All That Remains: A life in Death Alethea Mountford True crime is an increasingly popular topic for the masses, with countless television series, podcasts, magazines and books to choose from. For those who are interested in the nitty-gritty details as well as the science behind what goes on at a crime scene, All That Remains: A Life In Death takes you on a journey from learning anatomy and forensic pathology in the dissecting laboratory through to real life crime scenes. Professor Sue Black is a forensic anthropologist and anatomist who has been working within the field for over 30 years. She gives a perspective on her relationship with death from a personal, professional and scientific angle. Death affects everyone in one way or another, and although it may not be to everyone’s tastes, All That Remains certainly allows the reader to think about every aspect of the process from a different perspective.
34
{react} Issue 13 2020
Whether you are from a scientific background or not, spending a little time thinking about what truly makes us who we are, from a cellular to a cognitive level, is not necessarily a bad thing. The complexities of the human body are not only essential when it comes to living, but also when it comes to dying. When establishing a time and cause of death, our bodies offer up all of the clues that the professionals need to get a clear picture of
blogs.ncl.ac.uk/react
when and how things happen. The developments in understanding of the processes and timescales at which things happen have proved invaluable for explaining what happens after death.
All That Remains is definitely not for the faint of heart There are nearly 600 missing persons calls to the police every day in the UK, of which around half will go on to be recorded as officially missing. Whether or not the discovered missing person has been reported by family and friends, or is unreported, the challenges that face the forensic anthropologists who try to identify the body remain the same. Varying states of decay, a lack of identification documents and the possibility of fingerprints, DNA or dental records not being within the system can lead to significant delays in returning loved ones to their families. This also leaves the possibility of bodies never being identified, as is the case of the man from Balmore, whose remains were found in 2011 and whose identity is still a mystery.
Throughout the book, Black reminds us of the importance of thinking at the smallscale, of the individual, but also at the largescale, as in her experiences in Kosovo following the Račak massacre in January 1999. This chapter made for difficult reading, and it would perhaps be best to avoid reading it on public transport. From the trials of working at a scene that had been untouched for several months in 38° heat to uncovering and treating the remains of innocent adults and children with dignity in the face of the pressure of the press, Black relays her experiences in a respectful, yet at times light-hearted manner. Be warned, All That Remains is most definitely not for the squeamish or the faint of heart, but as Professor Black says, it’s better to deal with the devil you know.
If you’d like to learn more about Professor Sue Black and her work in the forensic anthropology and anatomy you can visit her website:
https://discovery.dundee.ac.uk/en/ persons/sue-black
Photo 152169800 © Nikola Mitic - Dreamstime.com
blogs.ncl.ac.uk/react
Issue 13 2020 {react}
35
FEATURE
Increasing disorder from a conformational change:
The history of Prion diseases Caitlin Griffiths
A simple definition of entropy is ‘the lack of order, or, the gradual decline into disorder’. This is not typically seen in biological sciences . Biological systems
until 1957 that the source of the disease was attributed to funerary cannibalism, where women and children would be expected to eat body parts, including the brain, of the
are governed by order. If one component
deceased. Although the number of cases of
cannot fulfil its role, the entire system can
kuru declined following the prevention of
be thrown into disorder. Occasionally this
cannibalistic rituals by the tribe, the exact
disorder can increase over time. In rare
cause was unknown for many years to
circumstances a change in the conformation
follow.
of a single protein can result in death. This is the case of prion disorders.
The mystery of transmissible spongiform encephalopathies (TSEs), like kuru, plagued
Prion disorders are best known for their
scientists since the first description of an
dark history. One of the most famous cases
uncharacterised human neurological
is that of the Fore tribe of Papa New
disorder by Hans Gerhard Creutzfeldt and
Guinea, who suffered from a disease they
Alfons Maria Jakob in 1920 and 1921
called ‘kuru’. The victims, commonly
respectively; Creutzfeldt-Jakob disease (or
women and children, first developed severe
CJD). In these diseases an infectious agent
tremors accompanied by uncontrolled
resides in the brain and remains infectious
sporadic laughter, before succumbing to
for years after death. A crude way in which
more severe symptoms such as ataxia (lack
this was first demonstrated was one
of voluntary coordination of muscle
scientist infecting a hamster with a TSE,
movements). The victims would typically
then burying its brain in the garden. Three
die within two years of showing the initial
years later when the brain was dug up, the
symptoms. Many tiny holes appeared in the
brain was still infectious.
cortex of the victim’s brain, making it appear like a sponge. The tribe originally believed that witchcraft or ghosts were 36
responsible for causing kuru. It was not
{react} Issue 13 2020
Due to the revelation around 1955 that viruses contained genetic information, and
blogs.ncl.ac.uk/react
that this conferred the ability for viruses to
protein (PrPC), a primarily alpha helical
be infectious, many scientists leapt upon
structure, undergoing a conformational
this theory to explain the cause of TSEs. The
change to a disease-causing isoform (PrPSc)
idea that a protein could be responsible for
with a structure rich in beta-pleated sheets.
an infectious disease went against the
This conversion promotes supramolecular
central dogma of biology. As a result,
association and gives PrPScs their
scientists went about trying to inactivate
propensity to aggregate. Although the exact
the agent that causes the TSE ‘scrapie’ in
reasons as to why this change in
sheep, using methods known to inactivate
conformation occurs are not fully
viruses and bacteria. Between 1964 and
understood, it is thought that the systems
1967 extreme heat, UV irradiation, high
responsible for assisting and controlling
pressures and numerous compounds were
biosynthesis of PrP may produce errors due
applied to the scrapie agent with limited
to age-related decreases in efficiency and
success in its inactivation. As a result, more
stringency. This may be why genetic prion
and more scientists began to speculate that
disorders often first present at a mature
the cause was in fact proteinaceous.
age. Following the conversion of one
It wasn’t until 1982 that the idea that a protein may be responsible for infection was more widely accepted. In that year, Stanley Prusiner isolated an infectious proteinaceous amyloid from scrapie-
molecule from PrPC to PrPSc the disorder begins to spread, with the infectious agent being able to ‘replicate’ itself, by converting correctly-folded prion protein into the infectious form.
infected animals, and successfully
Although it is an attractive hypothesis that
inactivated the infectious agent contained
PrPSc molecules interact with PrPC and
therein using methods that specifically
convert it to the infectious form, before the
destroyed proteins. Prusiner hypothesised that a singular protein, entering an altered conformation, caused TSEs like bovine spongiform encephalitis (BSE) and CJD, coining the term ‘prion’ to describe them. As a result of the wealth of supporting evidence that followed, Prusiner won the Nobel Prize in Physiology or Medicine in 1997. Our understanding of prion diseases has come a long way since the peak of kuru. There is evidence that prion disorders are a consequence of a normal cellular prion blogs.ncl.ac.uk/react
The change from alpha helix to beta sheet allows the prion to aggregate
Issue 13 2020 {react}
37
FEATURE two proteins separate and continue the process anew, PrPSc is not a particularly effective catalyst. Instead, a model more in line with in vivo data using transgenic mice suggests that PrPSc exists in fibrils (or thin fibres). The ends of the fibril can bind and convert one PrPC molecule at a time. The fibrils are thought to occasionally break, producing another infectious end, at which PrPC can bind. This may explain why CDC / Teresa Hammett
amyloid structures (protein aggregates with
Plaques in brain tissue affected by Creuzfeldt-Jakob disease
a fibrillar structure) are observed in the brain autopsies of victims. Recently, in 2016, one study identified that prion
been linked to the D178N mutation in the
proteins are responsible for neuron death
prion protein gene, PRNP, accompanied by
by shortening their dendritic spines and
a methionine at codon 129. Similarly, those
compromising transmission of signals,
with a genetic pre-disposition to CJD also
further explaining the neurological
carry the D178N mutation, but possess a
symptoms of prion diseases.
valine codon at amino acid 129 instead. However, CJD more often arises
Prion disorders are an unnerving example of how
spontaneously with sporadic CJD accounting for 85% of known cases. Globally, only 1 person per million per year
disorder, a change in the
is likely to develop CJD. Although this may
conformation of a single
sound reassuring, there is currently no
protein, can induce lethal and ever-increasing disorder
known cure for any of the prion disorders. .
Research on TSEs is underway, focussing on the biogenesis, propagation and spread of PrPs. The strides that have been made
Prion disorders can arise as a result of
since the first known case of TSE in 1920
genetic predisposition for PRP to change
give great hope that treatments for prion
conformation to the disease-associated
disorders will soon be developed.
PRP . This is the case for those suffering
However, for now prion disorders are an
from fatal familial insomnia (FFI), where
unnerving example of how an act of
patients initially suffer from severe
disorder, a change in the conformation of a
insomnia, followed by psychosis and
single protein, can induce lethal and ever-
eventual dementia. FFI predisposition has
increasing disorder.
C
Sc
38
{react} Issue 13 2020
blogs.ncl.ac.uk/react
What happens when the human body loses order? Maria O’ Hanlon The importance of homeostasis has been
tumours that typically contain a large varie-
stressed to scientists for generations. How-
ty of tissues including teeth, hair and
ever, it is easy to forget just how important homeostasis is, with this amazing mecha-
bones. They are also known as ovarian teratomas. Teratomas occur when skin struc-
nism being able to resist change in the body
tures become trapped during foetal devel-
in order to maintain a stable and relatively
opment. This could be due to a change in
constant internal environment. Sometimes
foetal body fluid homeostasis either due to
the importance of homeostasis only becomes apparent when something goes
exposure to teratogens, such as harmful chemicals, or an alteration in genetics.
wrong.
Dermoid ovarian cysts are rarely seen in
There are many diseases and problems that
practice as they are infrequent in women of
can arise due to homeostatic imbalance,
reproductive age, but smaller ones become
thanks to a loss of order and function within the body.
more common in the second or third decades of life. Giant ones, which are what
Ageing
would commonly be seen in histology laboratories, are extremely rare and sympto-
Unfortunately, normal ageing can affect
matic. These are associated with symptoms
homeostasis. Ageing is broadly defined as a decline and deterioration of function within
such as pain and increasing size around the abdominal area. The growing mass can
tissues and organs. Aged cells accumulate
cause the ovary to twist and impair its
damage over time, no longer responding to changes and losing function. This loss of
blood supply, potentially leading to rup-
function results in a loss of homeostasis and
ture and spillage of the contents within the body. While the majority of masses are be-
a decreased ability for the body to adapt to
nign, there are around 2% which will be-
both internal and external stresses. The un-
come malignant. Therefore, they will usual-
avoidable loss of homeostasis will lead to an increased vulnerability to disease and
ly be resected and removed from the body.
mortality.
This just highlights how important it is to maintain homeostasis.
Dermoid ovarian cysts
Infertility
One weird and wonderful example of disease caused by a loss of order is dermoid
An issue that many probably would not associate with homeostatic imbalance is
ovarian cysts. These are strange, benign
that of infertility. Homeostatic problems
blogs.ncl.ac.uk/react
Issue 13 2020 {react}
39
FEATURE can result in an imbalance in sexual hor-
example, a disruption in the immune sys-
mones which can lead to various disorders,
tem would lead to auto-immune destruction
such as infertility. These problems commonly arise from cancers. If there is a disruption
of beta cells in type 1 diabetes mellitus. Similarly, imbalance in the mechanism to con-
in homeostasis and a female patient has de-
trol insulin leads to insulin resistance in
veloped ovarian or breast cancer, removal
type 2 diabetes mellitus. . .
of the ovaries through a bilateral salpingooophorectomy may be recommended. The ovaries have two main reproductive
ance? . .
functions within the body. They produce
Maintenance of homeostasis is an essential
oocytes (eggs) during each menstrual cycle
part of sustaining a healthy but also a func-
for fertilisation alongside several female
tional life. Therefore, it is critical that there
hormones including progesterone and oestrogen. These hormones work together to
are measures in place to correct any imbalance before it becomes more destructive.
promote pregnancy. If there is a disruption
One of the most popular methods of correct-
with these hormones before the natural age of the menopause, women will enter prema-
ing homeostatic imbalance is hormone therapy. For example, when the ovaries must be
ture ovarian failure and the individual will be unable to conceive. The ovarian hor-
removed, an individual may be offered hor-
mones also help protect against certain other conditions. In fact, lack of female hor-
symptoms such as those associated with the menopause by replacing some of the hor-
mones will lead to a higher risk of developing osteoporosis because of impaired bone
mones the ovaries produced. Research into
development.
looking into this further is the Institute for
In men, the testicles must be kept at a stable
Genetic Medicine at the Centre for Life in Newcastle. For diabetes, reducing obesity
temperature. If this is disrupted, then the sperm will be destroyed, leading to problems with conception.
Diabetes The prevalence of diabetes has increased since the beginning of the 21st Century. Re-
40
How can we correct homeostatic imbal-
. .
mone replacement therapy to relieve any
infertility is an ongoing battle. One institute
and maintaining a healthy lifestyle can help to maintain a more normal state of homeostasis. Currently, it is not known how to correct homeostatic imbalance long-term, but it is manageable through drugs such as insulin in cases of diabetes. Hopefully in the
search has shown that this is tightly linked
future, researchers may be able to find a
with obesity, the cardiovascular system and
way to maintain this balance throughout
the kidneys. The relationship between these systems is the role of homeostasis. Diabetes
life. There are numerous diseases that can arise from homeostatic imbalance and a dis-
develops when there is a disruption of ener-
ruption in this usually flawless system real-
gy homeostasis. The form of the disease de-
ly highlights what happens when the body
pends on how the imbalance occurs. For
loses order.
{react} Issue 13 2020
blogs.ncl.ac.uk/react
FUN AND GAMES
Pick from the web Word search
blogs.ncl.ac.uk/react
Issue 13 2020 {react}
41
is recruiting! Roles include:
Layout and design Sub-editing articles Blogging
Managing social media . Get
in touch at
react.mag.team@gmail.com Book your places at workshops.ncl.ac.uk
